Tga presentation National Medicines Symposium 19 may 2016

Managing the Challenges and Opportunities of Breakthrough TherapiesWorkshop

Prudence Scott FRACP MPhil DPhilCo-Director, Haematology/Oncology Evaluation Unit, TGAMedical Oncologist, Monash Health

National Medicines Symposium, 19 May 2016


Goal of this workshop

• Foundations stream was asked to address the following:– Evidence– Safety– Knowledge– Quality

Goal: gather input, ideas, feedback on managing these key areas for medicines approved on early data


Pathway to registration ‘80s, ‘90s, 2000sPhase I, II and III clinical trials

Phase I: safety, tolerability, dose selection

Phase II: safety, efficacy, dose comparisons in range of cancers

Phase III: comparison with existing standard of care, used for registration


Emergence of targeted therapies 2001-

Drug or other substance that interferes with specific molecules involved in cancer cell growth and survival (NCI)

• “Driver mutations” or critical pathways• Specific populations• Biomarkers


Targeted therapiesSeamless oncology trials

• PK, PD, efficacy and safety• Expansion cohorts once dose-finding complete• Biomarker assessment

“Phase I” needs a new name:

suggestions?

• Studies of efficacy and safety• Multiple open label, single arm cohorts within Phase II trials - “octopus”• Master protocols• Biomarker validation +/- test development

Phase II

• ConfirmatoryPhase III


Regulatory response to unmet need 1992 FDA accelerated approval• unmet need• significant benefit over existing therapies• surrogate endpoint likely to predict clinical benefit• confirmatory data required• Label states in indication that approval is based on an early

endpoint and may require confirmation


Accelerated approvals in Haematology/Oncology

• Confirmation of benefit following accelerated approval– 50% confirmed– 40% still underway– 10% benefit not confirmed

reasons


Regulatory and advocate response to unmet need

FDA Breakthrough Designation 2012• Preliminary clinical data suggests a substantial benefit over existing

therapies for serious or life-threatening disease or condition• Access, support in clinical trial design from FDA• Accelerated approval not guaranteed


Breakthrough designations

338 in total137 (41%) in Haem Onc

38% granted38% denied20% withdrawn

201 (59%) other areas incl rare inherited disorders, ID


FDA pathway approvals in Haematology/Oncology

Of 46 new drugs approved in last 4 years (30 in last 2 years!)• 17 accelerated approval• 29 regular approval

• 19 had breakthrough designation


TGA submissions in Haematology/Oncology Registration in Australia now sought on earlier data for

Haematology/Oncology products

85%2014

75%2015


Opportunities from breakthrough designation

• Recognition of, resulted from patient voice• Earlier approval addressing unmet need• Ensures patients have access to optimally designed trials• What % of patients enter clinical trials in oncology?• Novel clinical trial designs emerging• Encourages and fosters innovation e.g. small pharma• New ways to use big data to analyse outcomes


Challenges with early approvals1. Rapid product development:

– Less known about safety and efficacy– Multiple trials still to report– Biomarker development, validation, testing may still be underway

Companion diagnostic vs complementary diagnostic– Incorporation of patient-reported outcomes eg PRO-CTCAE, COA Compendium

2. Collection, communication of post approval information– Patients, clinicians, regulators, sponsors, payers– Need reporting of adverse events by all stakeholders– Effective communication of updates

3. Timely completion of confirmatory trials and to act upon outcomes

4. Development of systems to capture big data e.g. INFORMED


Information Exchange and Data Transformation (INFORMED)

FDA Entrepreneur in Residence program • to support meta-analyses and other data explorations that can yield

groundbreaking scientific and regulatory insights• to create a big data environment comprised of aggregated datasets from:

– new drug applications (NDAs)– electronic medical records– wearable technologies – social media networks


Summary of breakthrough designation era

Better drugs

Better biomarkers

Less information


Communicating decision to approve on early data1. *Note to the Indication2. *Boxed warning in PI, equivalent in CMI3. Statement in Clinical Trials section re evidence base and further trials required to

be submitted as condition of registration (similar in CMI)4. Conditions of registration

– Confirmatory efficacy and safety Phase III study/studies– Marketing of note to the indication, boxed warning in any promotional materials

5. Post approval requirements – case-by-case– big data/real world data collection e.g. registries – key info for stakeholders– patient/doctor information cards– health professional educational material


Goal of this workshop

• Foundations stream was asked to address the following:– Evidence– Safety– Knowledge– Quality

Goal: gather input, ideas, feedback on managing these key areas for medicines approved on early data


Post approvalHow can we improve reporting of outcomes to the TGA?• immediately• longer term

How can registries capture efficacy and safety for medicines approved on early data?

How can the TGA communicate any necessary changes effectively to stakeholders?


Post approval

How can we improve reporting of outcomes to the TGA?• immediately• longer term


Post approval

How can the TGA communicate any necessary changes effectively to stakeholders?


Post approval

How can registries capture efficacy and safety for medicines approved on early data?


Post approval

Any other issues?

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Tga presentation National Medicines Symposium 19 may 2016

Health & Medicine